One of the fundamental nutritional paradoxes that all cells must cope with is the requirement for metals that are both essential for cellular function yet extremely toxic. The toxicity of these metals, in particular iron and copper, is based upon their redox activity and their ability to directly mediate the oxidation of macro-molecules (metal catalyzed oxidation) or to indirectly damage cells via the generation of reduced oxygen intermediates. Iron poses an addition problem for cells because, in the presence of oxygen, it is found in the insoluble ferric form. This project is aimed at understanding the molecular mechanisms responsible for the uptake, sensing, regulation, intracellular distribution, and utilization of these toxic but essential metals. This work has been approached using the simple eukaryote, Saccharomyces cerevisiae, which allows us to apply powerful molecular and genetic tools to the identification and characterization of essential components of metal metabolism. Through this approach, we have identified a series of genes whose function define the interlocking mechanisms by which both iron and copper are acquired from the environment by eukaryotic cells.